Aspects of the present application relate to pharmaceutical dosage forms containing particulate active ingredients that have limited water solubility. In embodiments, the dosage forms are intended to be administered orally to provide systemic absorption of an active ingredient from the gastrointestinal tract.
Much effort has been directed to improving the bioavailability and other pharmacological properties of drug substances. The needs are particularly acute for orally administered solid dosage forms of active ingredients that have limited solubility in water, since the gastrointestinal tract is a generally aqueous environment and many factors influence the ability of drug particles to become available for systemic absorption.
In general, it has been accepted that using smaller particles of an active pharmaceutical ingredient will enhance its oral bioavailability; rate of solubilization for particulate substances tend to increase as the particle sizes decrease, due to an increased particle surface area. However, using smaller particles in pharmaceutical dosage form production causes complications, since the smaller particles are not as easily handled. Flowability of particles frequently is lessened as their sizes decrease. Blending small particles with larger particles frequently results in poor uniformity of the blend. Also, various factors, including the surface electrical charges that can be present on small particles, promote undesired and unpredictable phenomena, such as agglomeration, that result in effectively increasing the original particle sizes during the handling and processing of powders.
U.S. Pat. No. 4,196,188 discloses difficulties encountered with the oral administration of progesterone in solid dosage forms. It is reported that compression of powders having small particle sizes results in modification of the granulometric distribution of the starting particles. The problems were overcome by providing a suspension of progesterone particles, at least 80% having sizes of 5-15 μm, in an oil vehicle that is filled into capsules. Such particle sizes were obtained by mixing recrystallized progesterone with arachid oil and milling the mixture in a cooled rotor mill that maintained temperatures of 25-30° C. Micronized progesterone is described as being very hygroscopic and electrostatic when the particles sizes are less than 20 μm, and exhibits particle size increases during storage that decrease drug bioavailability. This patent is believed to relate to the commercial product PROMETRIUM® progesterone capsules. However, use of the disclosed oil is presently not favored in pharmaceutical products, due to the prevalence of allergic reactions.
U.S. Pat. No. 4,927,816 discloses a sublingual capsule formulation comprising particles of progesterone having sizes less than 5 μm, in combination with a salivation stimulator.
U.S. Patent Application Publication No. 2004/0131553 discloses tablets containing a progestin, prepared by a procedure including co-micronizing the drug with a surfactant, preferably an ionic surfactant such as sodium lauryl sulfate. The co-micronization could involve dry ingredients, using a jet mill, or could be solid/liquid co-micronization, using a colloid mill or ball mill. According to this publication, micronizing the drug is not an automatic means for increasing bioavailability, as additional formulation development steps can be required; the effects of particle size reduction on solubility and bioavailability were said to be unpredictable.
U.S. Pat. No. 6,649,659 discloses the preparation of atovaquone suspensions, by passing an aqueous mixture containing 2.5 w/v atovaquone and 0.25% w/v Celacol™ M2500 (methyl cellulose) through a MICROFLUIDIZER™, producing suspensions having a mean drug particle size of 1 μm. The suspension had a higher drug bioavailability than another suspension having 3 μm mean size drug particles.
U.S. Pat. No. 6,248,363 discloses improving the dissolution and/or absorption of a number of drug substances, by coating a solution of a drug and a hydrophilic surfactant, or a mixture of hydrophilic and lipophilic surfactants, onto solid carrier particles. An example describes coating non-pareil seeds with a mixture of progesterone, a PEG-24 cholesterol ether (hydrophilic surfactant), and the lipophilic components distilled monoglycerides and deoxycholic acid.
U.S. Patent Application Publication No. 2005/0063913 discloses wet milling of metaxalone in the presence of povidone and docusate sodium, to prepare dispersions of nanoparticles of the drug.
The use of drug solutions for making solid dosage forms is not preferred, since the exact physical form of the drug in the finished dosage unit is not necessarily known or predictable. Also it is difficult to make soluble dosage form with acceptable size for oral administration due to poor solubility of drug in polymeric carriers or oils. A need remains for pharmaceutical dosage forms that contain low-solubility drug substances and have reproducible desired bioavailability characteristics.
There is a need to develop formulations having at least one of the following features:
i) Drugs can be produced as nanosuspensions with the smallest particle sizes in the range of 50 to 800 nm.
ii) Nanoparticles can maintain their primary particle sizes after downstream processing into solid pharmaceutical dosage forms.
iii) Drugs maintain supersaturation solubility profiles or superior dissolution characteristics, compared to their conventional oral dosage forms.